Clinical Outcomes for Metastatic Renal Cell Carcinoma (mRCC) Patients Ineligible for Front-line Clinical Trials

Clinical trials for immunotherapy-based regimens in metastatic renal cell carcinoma (mRCC) have extensive inclusion and exclusion criteria. We investigated the clinical outcomes in a real-world cohort of patients who would not have met the criteria for inclusion in front-line mRCC trials. Patients treated with ipilimumab/nivolumab and axitinib/pembrolizumab for front-line mRCC were identified and divided into clinical trial eligible (CTE) and clinical trial ineligible (CTI) cohorts based on key inclusion or exclusion criteria from their respective Phase-3 registration trials. Clinical outcomes were compared in CTE and CTI cohorts. A total of 62 patients treated with axitinib/pembrolizumab and 103 treated with ipilimumab/nivolumab were identified. The International Metastatic RCC Database Consortium (IMDC) criteria were similar across CTE and CTI patients in axitinib/pembrolizumab and ipilimumab/nivolumab cohorts. In the axitinib/pembrolizumab cohort (n = 62), 24 (39%) patients were CTI. The major reasons for the ineligibility were lab abnormalities (n = 11), histology (n = 9), and brain metastases (n = 3). There was no significant difference in response rates (P = 0.08). The median progression-free survival (PFS) was numerically longer in CTE patients (28 vs 12 months; P = 0.09). The overall survival (OS) was higher in the CTE patients (P = 0.02). In the ipilimumab/nivolumab cohort (n = 103), 59 (57%) were CTI. The most common reasons for ineligibility were brain metastases (n = 18), lab abnormalities (n = 16), and histology (n = 16). There was no significant difference in response rates (P = 0.22). However, PFS (P = 0.003) and OS (P < 0.0001) were higher in the CTE patients. In conclusion, many real-world patients are ineligible for RCC clinical trials and had worse outcomes when compared to trial-eligible patients. Additional treatment options are needed for these patients, as well as strategies to include them in prospective trials.


Introduction
There has been incredible progress in the treatment of patients with metastatic renal cell carcinoma (mRCC).This is largely a result of the introduction of immunotherapy-based combinations for patients with treatment-naïve mRCC.These regimens have a checkpoint inhibitor (CPI) immuno-oncology (IO) agent backbone in combination with either another IO agent (IO/IO) or a vascular endothelial growth factor receptor tyrosine kinase inhibitor (IO/TKI).The FDA has approved five such combinations for patients with treatment-naïve clear cell mRCC.These included one IO/IO combination (ipilimumab/nivolumab) and four IO/ TKI combinations (axitinib/pembrolizumab, axitinib/avelumab, cabozantinib/nivolumab, and lenvatinib/pembrolizumab) (1)(2)(3)(4)(5).
However, it is well-established that the positive clinical trial results that lead to regulatory approval are not always replicated in real-world clinical practice (6).Several reasons for this phenomenon have been described including, but limited to, issues related to clinical trial design, data interpretation, conflicts of interest, and biological heterogeneity between clinical trials and real-world clinical practice (6,7).A primary concern often raised about the applicability and relevance of clinical trial results to the broader population relates to the restrictive inclusion and exclusion criteria in clinical trial design that do not reflect the real-world clinical population (8).It is unclear whether these restrictive eligibility criteria are clinically meaningful and impact patient outcomes.This study therefore investigated the clinical outcomes in a real-world cohort of patients who would not have met the criteria for inclusion in front-line mRCC trials.

Materials and Methods
Patients at Cleveland Clinic, treated with ipilimumab/ nivolumab or axitinib/pembrolizumab from July 2014 to February 2021 for front-line mRCC were identified.They were classified as clinical trial eligible (CTE) and clinical trial ineligible (CTI) cohorts based on key inclusion or exclusion criteria from their respective Phase-3 registration trials (CheckMate 214 and KEYNOTE-426) (1,5).Patient-and disease-specific features were analyzed, and reasons for trial ineligibility were identified.
The summary of patient characteristics was provided in median, IQR, and range for continuous variables, and in frequencies and percentages for categorical variables.The overall survival (OS) and progression-free survival (PFS) were calculated from IO start date to death or last follow-up (LFU) date for OS, and to progression date, death, or LFU date for PFS.Kaplan-Meier method was used to estimate the OS and PFS.Log-rank test was used to compare OS and PFS between patient groups.Statistical analysis was performed using SAS Studio 3.7 (SAS Institute, Cary, NC) and R version 4.2 (R Foundation, Vienna, Austria).

Baseline characteristics
A total of 62 patients treated with axitinib/pembrolizumab and 103 treated with ipilimumab/nivolumab were identified.The baseline characteristics were reflective of a typical mRCC cohort (Table 1).In the axitinib/pembrolizumab cohort, most of the patients were men (71%).The median age was 62.6 (40.2-88.3),with 82% clear cell histology, and most (58%) of them had an intermediate risk per the International Metastatic RCC Database Consortium (IMDC) criteria.Similarly, in the ipilimumab/nivolumab cohort, most patients were men (76%).The median age was 62.0 (26.8-87.7),with 80% clear cell histology, and most (58%) of them fell under the category of intermediate risk as per IMDC (Table 1).
There was no difference in clinical trial eligibility based on IMDC risk criteria.Patients who had a prior nephrectomy were more likely to be CTE in both the axitinib/pembrolizumab (P = 0.01) and the ipilimumab/nivolumab (P = 0.04) cohorts.The presence of bone metastasis was associated with CTI status in the axitinib/pembrolizumab cohort (P = 0.03) but not in the ipilimumab/nivolumab patients (P = 0.67).The reverse was observed with liver metastasis, which was associated with CTI status only in the ipilimumab/nivolumab cohort (P = 0.002).
A multivariable Cox model for OS and PFS by cohort was also performed (Table 4).Trial ineligible patients had significantly worse OS and PFS in the ipilimumab/nivolumab cohort, after adjusting for age, gender, and IMDC.However, the CTE status was not statistically significant for OS or PFS in axitinib/pembrolizumab cohort after adjusting for age, gender, and IMDC.The statistical power was limited for axitinib/pembrolizumab cohort due to smaller sample sizes and number of events.

Discussion
The introduction of immunotherapy-based combinations for patients with treatment-naïve mRCC has revolutionized the care of these patients and significantly improved OS.However, the restrictive inclusion and exclusion criteria for these trials result in clinical outcomes that may not be reproducible in the real-world setting (6,7).In this analysis, patients with treatment-naïve mRCC treated with ipilimumab/nivolumab or axitinib/pembrolizumab who would not have met their respective registration clinical trial eligibility criteria had worse outcomes than those who would have met clinical trial criteria.The percentage of patients who would have been ineligible for the registration trials was relatively high for both axitinib/pembrolizumab and ipilimumab/ nivolumab cohorts, at 39% and 57%, respectively.There are two primary consequences to the overly restrictive eligibility criteria in clinical trials.First, they limit enrolment to clinical trials, which delays potential advances in drug development and approval.The second concern is that limiting clinical trial enrolment based on strict eligibility criteria may be self-selective for a generally healthier patient population that does not reflect the real-world population to which these therapies will ultimately be applied.
These concerns have resulted in ongoing efforts to relax clinical trial eligibility and broaden the population who may subsequently participate in clinical trials.The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research established working groups that proposed several recommendations to make clinical trials more representative and inclusive (9).In broad terms, the proposal recommends only excluding patients from clinical trials if there is a compelling scientific rationale or evidence that a patient's safety would be compromised by enrollment, inclusion and exclusion criteria be tailored to the study objectives, and that the study population more closely resemble the real-world populations without excluding specific groups in the absence of scientific justification.More specifically, this working group

Table 2 :
Reasons for exclusion from clinical trials.